Congenital malformations are the leading cause of infant morbidity and mortality in the United States. Despite the overwhelming significance of this problem, the etiology of most congenital malformations remains elusive. The long-term objective of this research is to understand the developmental and genetic basis of human malformations. The studies in this current proposal are intended to elucidate the mechanisms of bone growth and development. Specifically, a multi-disciplinary, synergistic program of basic and clinical scientists will focus on the common central theme of skeletal morphogenesis through the critical analysis of several unique animal models and patients. In Project I, Stephen Johnson (Genetics) will utilize zebrafish to define the genes involved in local and systematic control of fin growth and morphogenesis. In Project II, David Ornitz (Pharmacology) will determine the specific role of the fibroblast growth factor receptors (FGFRs) in endochondral bone growth and development and define the biochemical mechanisms of a mutation in FGFR2 resulting in Apert syndrome. In Project II, Scott Saunders (Pediatrics) will utilize a novel murine model of Simpson-Golabi-Behmel (SGB) syndrome to define the role of heparan sulfate proteoglycans in bone growth and differentiation and undertake genotype/phenotype analysis of affected SGB patients focusing on the abnormalities in skeletal growth and development and development. In Project IV. Jonathan Gitlin (Pediatrics) will examine the mechanisms of in utero genetic deprivation of cooper on the disruption of modification on genes determining skeletal growth and development. A bioinformatics/microarray research core under the direction of Bernard Brownstein (Genetics) will be utilized by all investigators to define and characterize novel genetic programs essential for skeletal growth and morphogenesis in the animal models being studied. An administrative core will coordinate scientific activities and resources. Taken together, the results of this interactive collaboration of basic and clinical scientists will permit new insights into the mechanisms of skeletal growth and may allow for the translational development of novel strategies to prevent, ameliorate and treat human malformations.